Background: Preclinical models have shown that autophagy is a cell survival mechanism to overcome treatment-induced stress and facilitate progression and resistance in CRPC. Metformin (met) demonstrates autophagy inhibition and resensitizes CRPC tumors to enzalutamide (enza) as a combination in in vitro models. A Phase Ib/II trial was conducted to evaluate the combination. Methods: Eligible patients (pts) had established CRPC, ECOG 0-2, adequate hematologic and organ function, and ≤ 2 prior treatments for CRPC. Major exclusion criteria included prior enza or met treatment, presence of brain metastases, history of DM2 or seizures. An initial cohort of 3 pts were treated with enza 160 mg PO daily and met 500 mg PO bid (DL1), with met dose escalated to 1000 mg PO bid (DL2) in subsequent 3 pts if dose-limiting toxicity (DLT) was observed in ≤1 pt in DL 1, and cycles of 28 days. Once primary objective of maximum tolerated dose (MTD) was established, additional pts were enrolled at MTD for a total of 24 evaluable pts. Secondary objectives of the study included PSA response and safety. Results: From 8/24/16-12/31/18, a total of 3 pts were enrolled to DL1, with no DLTs observed in that cohort, with an additional 21 enrolled to DL2; 12 remain on trial. Median age was 71, with 8/24 (33%) and 3/24 (12.5%) with prior docetaxel and abiraterone treatment, respectively. One DLT due to Grade 3 abdominal pain was observed at DL2 prior to establishing MTD. Grade 3 AEs observed in 1/24 (4%) of pts were diarrhea, fatigue, hypertension, lower GI bleed, myalgia; 2/24 (8%) had abdominal pain. One pt had Grade 4 hallucinations. Among pts who discontinued, 8 were discontinued for progression, 3 withdrew consent, and 1 experienced an SAE (seizure). Pts received median of 11 cycles (1-31) of treatment. PSA response ≥ 50% was observed in 19/24 (79%) pts. Conclusions: The combination of enzalutamide 160 mg PO daily and metformin 1000 mg PO bid is well-tolerated, and clinically active. Clinical trial information: NCT02339168